BLOCKADE OF VOLTAGE-SENSITIVE SODIUM-CHANNELS BY NS-7, A NOVEL NEUROPROTECTIVE COMPOUND, IN THE RAT-BRAIN

The effects of 4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyri midine hydrochloride (NS-7), a novel neuroprotective compound, on the voltage-sensitive sodium channels (VSSC) were examined in the rat brai n and cardiac myocytes. NS-7 inhibited [H-3]batrachotoxinin A 20 alpha -benzoate (BTX) binding (neurotoxin receptor site 2) in brain membrane s with a Ki value of 1 mu M, while the compound was less effective in the cardiac myocytes (Ki = 13 mu M). Aconitine, on the other hand, inh ibited [H-3]BTX binding to brain membranes and cardiac myocytes with t he same potency. In contrast, NS-7 had no affinity for [H-3]saxitoxin binding in brain (neurotoxin receptor site 1). In superfused slices of the rat cerebral cortex, NS-7 inhibited the veratridine (5 mu M)-evok ed glutamate release in a concentration-dependent manner, the IC50 val ue of which was 7.7 mu M, whereas the compound showed a weak and not s ignificant suppression of KCl-evoked glutamate release. The tissue con centrations of NS-7 in the rat cerebral cortex and heart were 89 and 2 8 nmole/g tissue, respectively, 5 min after its intravenous injection (8 mg/kg). Furthermore, in the cerebral cortex, NS-7 distributed prefe rentially to the membrane-enriched synaptosomal fraction. Since neurot oxin receptor site 2 is located in the transmembrane region of the VSS C moiety, the channel function may be substantially inhibited by a per ipheral administration of NS-7. These results suggest that the blockad e of neurotoxin receptor site 2 of VSSC in the brain contributes to th e neuroprotective action of NS-7.